Low Doses of Silver Nanoparticles Selectively Induce Lipid Peroxidation and Proteotoxic Stress in Mesenchymal Subtypes of Triple-Negative Breast Cancer

Molecular profiling of tumors shows that triple-negative breast cancer (TNBC) can be stratified into mesenchymal (claudin-low breast cancer; CLBC) and epithelial subtypes (basal-like breast cancer; BLBC). Subtypes differ in underlying genetics and in response to therapeutics. Several reports indicate that therapeutic strategies that induce lipid peroxidation or proteotoxicity may be particularly effective for various cancers with a mesenchymal phenotype such as CLBC, for which no specific treatment regimens exist and outcomes are poor. We hypothesized that silver nanoparticles (AgNPs) can induce proteotoxic stress and cause lipid peroxidation to a greater extent in CLBC than in BLBC. We found that AgNPs were lethal to CLBCs at doses that had little effect on BLBCs and were non-toxic to normal breast epithelial cells. Analysis of mRNA profiles indicated that sensitivity to AgNPs correlated with expression of multiple CLBC-associated genes. There was no correlation between sensitivity to AgNPs and sensitivity to silver cations, uptake of AgNPs, or proliferation rate, indicating that there are other molecular factors driving sensitivity to AgNPs. Mechanistically, we found that the differences in sensitivity of CLBC and BLBC cells to AgNPs were driven by peroxidation of lipids, protein oxidation and aggregation, and subsequent proteotoxic stress and apoptotic signaling, which were induced in AgNP-treated CLBC cells, but not in BLBC cells. This study shows AgNPs are a specific treatment for CLBC and indicates that stratification of TNBC subtypes may lead to improved outcomes for other therapeutics with similar mechanisms of action.

Scavenging Reactive Lipids to Prevent Oxidative Injury

Oxidative injury due to elevated levels of reactive oxygen species is implicated in cardiovascular diseases, Alzheimer's disease, lung and liver diseases, and many cancers. Antioxidant therapies have generally been ineffective at treating these diseases, potentially due to ineffective doses but also due to interference with critical host defense and signaling processes. Therefore, alternative strategies to prevent oxidative injury are needed. Elevated levels of reactive oxygen species induce lipid peroxidation, generating reactive lipid dicarbonyls. These lipid oxidation products may be the most salient mediators of oxidative injury, as they cause cellular and organ dysfunction by adducting to proteins, lipids, and DNA. Small-molecule compounds have been developed in the past decade to selectively and effectively scavenge these reactive lipid dicarbonyls. This review outlines evidence supporting the role of lipid dicarbonyls in disease pathogenesis, as well as preclinical data supporting the efficacy of novel dicarbonyl scavengers in treating or preventing disease.

PALP: An imaging method for detecting and quantifying polyunsaturated phospholipids via peroxidation

ABSTRACTPolyunsaturated phospholipids are essential for multiple cellular functions; however, their uncontrolled peroxidation leads to ferroptosis. Here we describe photochemical activation of membrane lipid peroxidation (PALP), which uses localized laser pulses to induce lipid peroxidation photochemically. While PALP bypasses enzymatic requirements for lipid peroxidation, the resulting BODIPY-C11-based signal is largely correlated with local polyunsaturated phospholipid concentration on membranes. This technique enables non-invasive reporting of lipid unsaturation levels and sensitivity to ferroptosis in live cells.

Effect of Superoxide Dismutase (SOD) Supplementation on Plasma Levels of Malondialdehyde (MDA), Total Cholesterol and LDL Cholesterol in the Elderly

Background: Several various physiological functions in elderly people are diminished due to cell or tissue damage. One of the probable causes are oxidative stress yielded by free radicals.Oxidative stress (ROS) induce lipid peroxidation in endothelial cell membrane, which generates atherosclerotic plaque. In a state of oxidative stress, MDA level will increased. The purpose of this study is to determine the effect of SOD supplementation on MDA, total cholesterol and LDL cholesterol plasma levels in the elderly.Methods: This study was open label, a randomized control trial. Subjects were elderly people aged > 60 years (median 75, 60-82 ys, male 10 (24,4%)) institutionalized at Social Rehabilitation Unit Pucang Gading Semarang, Indonesia. The treatment group consisted of 16 people, received SOD (GlisodinR) 1 capsule (250 IU) 1 hour before meals, plus exercise scheduled for 8 weeks. The control group consisted of 15 people, received placebo, and exercise. Plasma MDA levels were examined using TBARS method, while total cholesterol and LDL cholesterol were examined using CHOD-PAP method.Results: This study show a reduction of plasma MDA levels in the treatment group compare to control group ( p = 0.062 ). A significant reduction of total cholesterol and LDL cholesterol levels in the treatment group were found (before 190.00 and 131.47 g/dl, after 182.27 and 121.93 g/dl, p = 0.005 and 0.001).Conclusion: The SOD supplementation significantly reduce Total Cholesterol and LDL level, but not MDA level in the elderly.

Effect of Dietary Probiotics(Saccharomyces cerevisae)Supplementation on Serum Biochemicals ofTrypanosoma brucei bruceiInfected Rats

Background:Trypanosomosis is an important disease of both humans and animals commonly found in most parts of Africa and South America. Because of their activities, the parasites produce numerous changes in the cellular and biochemical constituents of blood. Also, trypanosomosis cause immunosuppression and also induce lipid peroxidation in the host. Probiotics confer beneficial health benefit to the host such as immune stimulation, protection against pathogens, metabolism, reduced oxidative stress, etc.Methods:Thirty (30) adult albino rats were assigned into 5 groups (A – E) of 6 rats each. Groups A, B and C rats were fed feed supplemented with probiotics at 0.08, 0.12 and 0.16 mg per kg respectively. On day 14 on the supplementation (OTS), groups A, B, C and D rats were infected with 1 x 106 trypanosomes intraperitonealy. Group E served as the not infected, not supplemented control.Results:The pre-infection supplementation did not vary the serum alanine transaminase (ALT), aspartrate transaminase (AST), urea, creatinine and total protein values of groups A, B and C. However, following infection, the ALT value of group D (infected, not supplemented) was significantly (p<0.05) higher than other groups on day 42 OTS. Also, the AST value of groups A and D were significantly (p<0.05) higher than group E but not with groups B and C on days 42 and 56 on the supplementation. On day 28 OTS, the urea level of group B was significantly (p<0.05) lower than group D whereas on days 42 and 56, group E and groups E and C were significantly (p<0.05) lower than other groups respectively. The serum creatinine level showed increase following infection with groups A and D being significantly (p<0.05) higher than other groups on days 42 and 56 OTS. On day 28 OTS, the total protein value of group A was significantly (p<0.05) lower than group C but not with other groups. By days 42 and 56 OTS, group D showed significantly (p<0.05) lower protein level when compared with other groups. The mean parasitaemia level of group D was significantly higher than other infected infected groups on days 28 and 42 on the supplementation. However, on day 56, the parasitaemia level of all infected groups did not vary (p>0.05).Conclusion:The ability of the supplementation to keep serum biochemical values before infection within range, and the subsequent maintenance of the value during most part of the infection were indication that probiotic was not toxic and may play a vital role in management of trypanosomosis.

Oxidative stress in neonates with hyperbilirubinemia before and after phototherapy: malondialdehyde and catalase activity

Background Phototherapy is used to treat neonatal hyperbilirubinemia, but is currently thought to cause photodynamic stress and can induce lipid peroxidation. There is increasing evidence that many severe diseases of the neonates are caused by oxidative injury and lipid peroxidation. In the present communique, we review the oxidative succeptibility of the neonate and the evidence now available that phototherapy induces oxidative stress. Malondialdehyde (MDA) is a metabolic product of free radicals. Catalase is a antioxidant that binds free radicals. Objective To compare the levels of oxidants and antioxidants before and after phototherapy in neonates with hyperbilirubinemia. Methods This pretest-posttest control group study was conducted in Sanglah Hospital, Bali from November 2016 to April 2017. Thirty babies with gestational age ≥35 weeks and hyperbilirubinemia with total bilirubin levels requiring phototherapy were included in this study. The MDA levels and catalase activity were measured before and after 24 hours of phototherapy. Results Comparative analysis using paired T-test showed a significant increase of malondialdehyde level, with mean MDA 23.73 (SD 8.20) nmol/mL before and 53.05 (SD 10.18) nmol/mL after phototherapy (P<0.001). However, catalase activity significantly decreased from of 72.33 (SD 10.63) kU/L before phototherapy to 44.85 (SD 14.79) kU/L after phototherapy (P<0.001). The MDA level had a significant, negative association with catalase activity after phototherapy (r =-0.4; P=0.028). Conclusion Neonates with hyperbilirubinemia are found to have increased oxidative stress after phototherapy, as indicated by increased MDA levels and decreased CAT activity after 24 hours of phototherapy.

Local salt substitutes “Obu-otoyo” activate acetylcholinesterase and butyrylcholinesterase and induce lipid peroxidation in rat brain

Evidence has shown that ingestion of heavy metals can lead to neurodegenerative diseases. This study aimed to investigate the neurotoxic potential of salt substitutes (Obu-Otoyo); salt A (made by burning palm kernel shaft then soaked in water overnight and the extract from the resulting residue is used as the salt substitute) and salt B (an unrefined salt mined from a local site at Ilobu town, Osun-State, Nigeria) by assessing their effect on some key enzymes linked with neurodegenerative disease [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities] as well as on malondialdehyde (MDA) content of the rat brain. Salt substitutes were fed to normal rats as dietary inclusion at doses of 0.5 and 1.0% for 30 days. Thereafter, the effect of the salt substitutes on AChE and BChE activities as well as on MDA level in the rat brain was determined. The results revealed that the salt substitutes caused a significant (p<0.05) increase in both AChE and BChE activity and also induced lipid peroxidation in the brain of rats in vivo as well as under in vitro condition in a dose-dependent manner. The effect of the salt substitutes on AChE and BChE activities could be attributed to the presence of some toxic heavy metals. Therefore, the ability of the salt substitutes to induce lipid peroxidation and activate AChE and BChE activities could provide some possible mechanism for their neurotoxic effect.

Late-stage systemic immune effectors in Plasmodium berghei ANKA infection: biopterin and oxidative stress

To investigate the involvement of systemic oxidative stress in the pathogenesis of murine cerebral malaria, mice were infected with the Plasmodium berghei (P. berghei) ANKA 6653 strain. Serum tryptophan (Trp), kynurenine and urinary biopterin, liver, brain, spleen and serum superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) and nitrite and nitrate (NOx) levels were measured on day 7 post-inoculation. Our data showed a significant decrease in SOD and an increase in GPx activity and MDA level in all the examined biological materials (p<0.05), except spleen. Conversely, GPx activities in spleen were depleted, while SOD and MDA levels remained unchanged. Increased MDA levels might indicate increased peroxynitrite production, lipid peroxidation and oxidative stress. Also, elevated urinary biopterin, which was accompanied by increased NOx (p<0.05), may support the inhibition of Trp degradation (p>0.05). The excessive NO synthesis in P. berghei infection may be related to the up-regulation of inducible NO synthase, which was in accordance with the increased biopterin excretion. Thus, the large quantities of released toxic redox active radicals attack cell membranes and induce lipid peroxidation. Although P. berghei infection did not demonstrate systemic Trp degradation and related indoleamine-2,3-dioxygenase activity, it may cause multi-organ failure and death, owing to host-derived severe oxidative stress.

Fatal aluminium phosphide poisoning

Aluminium phosphide (AlP) is a cheap solid fumigant and a highly toxic pesticide which is commonly used for grain preservation. AlP has currently aroused interest with a rising number of cases in the past four decades due to increased use for agricultural and non-agricultural purposes. Its easy availability in the markets has increased also its misuse for committing suicide. Phosphine inhibits cellular oxygen utilization and can induce lipid peroxidation. Poisoning with AlP has often occurred in attempts to commit suicide, and that more often in adults than in teenagers. This is a case of suicidal consumption of aluminium phosphide by a 32-year-old young medical anesthetist. Toxicological analyses detected aluminium phosphide. We believe that free access of celphos tablets in grain markets should be prohibited by law.